DESCRIPTION: The neural substrate that bridges the stimulus free trace interval during acquisition and consolidation of forebrain-dependent trace eyeblink conditioning (EBC) is still unknown, but likely to involve the prefrontal cortex according to our previous lesion studies and several single neuron recording studies in non-human primates during delay matching to sample tasks. The goal of this proposal is to define the role of interactions between the prefrontal cortex and thalamic nuclei in mediating acquisition and consolidation of the trace eyeblink conditioning task in rabbits. This goal will test the hypothesis that the prefrontal cortex utilizes feedback from the hippocampus and cerebellum via the anteroventral (AV) and ventral anterior (VA) thalamus respectively, as well as projections with the dorsomedial (MD) thalamus to maintain neural activity during the stimulus free trace interval that we place between the conditioned and unconditioned stimuli (CS &US). Several aims are proposed to achieve this goal. The first aim is to determine if reversible inactivations of the rabbit dlPFC prevent or abolish learning of trace EBC. The second aim is to determine the rabbit homologue of the primate dorsolateral prefrontal cortex (dlPFC) using tract tracing techniques and fMRI. The third aim is to use multiple single neuron recordings to determine if neurons in the dlPFC exhibit learning-specific increases in response magnitude and duration that might mediate the trace interval. The fourth aim is to examine with multiple single neuron recordings the response properties of neurons within the different thalamic nuclei, especially the dorsomedial (MD) thalamus that projects to the dlPFC, the anteroventral (AV) nucleus of the thalamus which is at the junction of the hippocampal formation and the frontal cortex, and the ventral anterior (VA) thalamus which receives feedback from the cerebellar nucleus and projects into the basal ganglia. These aims will be done while recording extension of the nictitating membrane to monitor behavior. This experimental program will use a combination of trace eyeblink conditioning with a whisker vibration CS (to take advantage of the somatotopic arrangement of the whisker barrel cortex), multiple single neuron recording from several sites, reversible inactivations with muscimol, functional magnetic resonance imaging (fMRI), and tract tracing with WGA-HRP and MnCl2 (a "tract tracer" that is visible with MRI) to define and determine the role of the rabbit dlPFC and the mechanisms of thalamo-cortico interactions on forebrain- and cerebellar- dependent trace EBC. Comparisons of stimulus evoked changes in neuronal firing rates will be compared with similar data collected from control rabbits that receive explicitly unpaired presentations of the CS and US in order to asses changes related to learning. PUBLIC HEALTH RELEVANCE The results of this research program should lead to a better understanding of forebrain-cerebellar interactions including the role of the prefrontal cortex (which is likely to be involved in age-related learning and memory impairments) and the cognitive thalamic nuclei (which appear to be intimately involved with the neural mechanisms mediating drug addiction and schizophrenia).